Defining the Functional Effects of Titin Gene Mutations on the Pathophysiology of Dilated Cardiomyopathy and their Clinical Significance

确定 Titin 基因突变对扩张型心肌病病理生理学的功能影响及其临床意义

• 批准号: MR/M003191/1
• 负责人: Upasana Tayal
• 金额: $ 27.88万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM003191%2F1
• 关键词: Defining; Functional; Effects; Titin; Gene

Heart failure affects over 750,000 people in the UK. Dilated cardiomyopathy (DCM) is the second commonest cause and occurs in up to 1 in every 500 people. What is dilated cardiomyopathy? Dilated cardiomyopathy is a condition where the heart muscle becomes weaker (cardiomyopathy) and the heart becomes bigger (dilated). People can develop problems with fluid on their lungs, dangerous heart rhythms, and in some cases, ultimately a heart weak enough to need replacing with a transplant.In the vast majority of cases, we do not fully understand what causes the damage to the heart in the first place. This means that we do not have any targeted treatments to offer these patients. We currently use the same medicines in all patients with weak heart muscle, whatever the cause. Unfortunately, people with this condition may not have any symptoms until very advanced stages of the disease which means that the treatment we do have may not be able to do very much to repair or halt the damage to the heart. What is this research trying to achieve?Recent work done by researchers in our group, working with collaborators at Harvard University, has shown that a quarter of people who we previously thought had no identifiable cause for the weak heart, had an abnormality in a gene (called TTN) responsible for making the biggest protein in heart muscle (titin). We would like to study in more detail what it means for people who carry this gene.Who is doing this research? This work is a collaboration between the cardiac MRI imaging department at the Royal Brompton Hospital and the genetics team at the Royal Brompton and Imperial College in London. Together, Imperial College and the Royal Brompton Hospital form the largest specialist heart and lung centre in the UK. They have an internationally renowned research reputation and are best placed to conduct this research. The discovery of the abnormal gene (TTN) that forms a key part of this research was done in collaborative work by one of the research supervisors. How are we going to do this research? We would like to use an advanced scan of the heart called cardiac MRI to see if there is a pattern of disease in the heart muscle of patients with the abnormal gene. We will invite our patients who we know have both dilated cardiomyopathy and the abnormal TTN gene to have an MRI scan of their heart. MRI scans of the heart are very good at looking at the detailed structure of the heart muscle and can pick up changes that other tests (for example echocardiograms) cannot. MRI scans are safe, non invasive and painless tests. On the MRI scan, we will look for early signs of disease such as scarring in the heart - called fibrosis and abnormalities in the blood supply (microcirculation).We know that the abnormal gene can run in families so we will also invite the relatives of people with dilated cardiomyopathy to be tested for the abnormal gene. If they have the abnormal gene we will offer them the opportunity to have an MRI scan of their heart to see if they have any subtle changes in their heart, even when they do not have any symptoms. Why is this important? Crucially, once we have done the detailed MRI scan, we will also follow up the patients with dilated cardiomyopathy to see if we can identify any particular patterns in their genes or scans that are associated with a worse outcome in the long term. If this is the case, then we may be able to offer these patients earlier and more intensive treatment in the future to help prevent them from ending up with severe disease and this information might also help us to develop new treatments.For those people who feel well but have been told they have the abnormal gene, we will see if there are any early signs of heart disease on their scans. If this is the case, then in the future, we may be able to start them on the right treatment sooner to avoid progressing to advanced disease and keeping their hearts healthy.

英国有超过75万人患有心力衰竭。扩张型心肌病（DCM）是第二大常见原因，每500人中就有1人发病。什么是扩张型心肌病？扩张型心肌病是心肌变弱（心肌病）和心脏变大（扩张）的一种情况。人们可能会出现肺部积液问题，心率危险，在某些情况下，最终心脏虚弱到需要移植。在绝大多数情况下，我们首先并不完全了解是什么导致了心脏损伤。这意味着我们没有任何针对这些患者的治疗方法。我们目前对所有心肌虚弱的病人使用同样的药物，不管原因是什么。不幸的是，患有这种疾病的人可能直到疾病的晚期才会出现任何症状，这意味着我们现有的治疗方法可能无法修复或停止对心脏的损害。这项研究想要达到什么目的？我们小组的研究人员与哈佛大学的合作者最近所做的工作表明，在我们以前认为没有明确原因导致心脏虚弱的人中，有四分之一的人在一个基因（称为TTN）上有异常，该基因负责制造心肌中最大的蛋白质（titin）。我们想更详细地研究这对携带这种基因的人意味着什么。谁在做这项研究？这项工作是皇家布朗普顿医院心脏核磁共振成像部门与皇家布朗普顿和伦敦帝国理工学院的遗传学团队合作完成的。帝国理工学院和皇家布朗普顿医院共同组成了英国最大的专业心肺中心。他们拥有国际知名的研究声誉，是开展这项研究的最佳人选。异常基因（TTN）的发现是本研究的关键部分，是由一位研究主管合作完成的。我们要怎么做这个研究呢？我们想使用一种叫做心脏核磁共振成像的高级心脏扫描技术，来观察携带异常基因的患者的心肌是否存在某种疾病模式。我们会邀请那些同时患有扩张型心肌病和异常TTN基因的病人对他们的心脏进行核磁共振扫描。心脏的核磁共振扫描可以很好地观察到心肌的详细结构，并且可以发现其他测试（例如超声心动图）无法发现的变化。核磁共振扫描是一种安全、无创、无痛的检查。在核磁共振扫描中，我们将寻找疾病的早期迹象，如心脏瘢痕（称为纤维化）和血液供应（微循环）异常。我们知道异常基因可以在家族中遗传，所以我们也会邀请扩张型心肌病患者的亲属进行异常基因检测。如果他们有异常基因，我们会给他们提供机会对他们的心脏进行核磁共振扫描，看看他们的心脏是否有任何细微的变化，即使他们没有任何症状。为什么这很重要？至关重要的是，一旦我们完成了详细的核磁共振扫描，我们还将对扩张型心肌病患者进行随访，看看我们是否能在他们的基因或扫描中识别出任何与长期不良结果相关的特定模式。如果是这样的话，那么我们可能能够在未来为这些患者提供更早和更强化的治疗，以帮助防止他们患上严重的疾病，这些信息也可能有助于我们开发新的治疗方法。对于那些感觉良好但被告知有异常基因的人，我们将在他们的扫描中看到是否有任何心脏病的早期迹象。如果是这样的话，那么在未来，我们可能能够更快地开始正确的治疗，以避免进展到晚期疾病，并保持他们的心脏健康。

项目成果

Sex- and age-based differences in the natural history and outcome of dilated cardiomyopathy.

基于性别和年龄的自然病史和扩张心肌病的结果。

• DOI: 10.1002/ejhf.1216
• 发表时间: 2018-10
• 期刊: European journal of heart failure
• 影响因子: 18.2
• 作者: Halliday BP;Gulati A;Ali A;Newsome S;Lota A;Tayal U;Vassiliou VS;Arzanauskaite M;Izgi C;Krishnathasan K;Singhal A;Chiew K;Gregson J;Frenneaux MP;Cook SA;Pennell DJ;Collins P;Cleland JGF;Prasad SK
• 通讯作者: Prasad SK

Adverse prognosis associated with asymmetric myocardial thickening in aortic stenosis.

• DOI: 10.1093/ehjci/jex052
• 发表时间: 2018-03-01
• 期刊: European heart journal. Cardiovascular Imaging
• 作者: Kwiecinski J;Chin CWL;Everett RJ;White AC;Semple S;Yeung E;Jenkins WJ;Shah ASV;Koo M;Mirsadraee S;Lang CC;Mills N;Prasad SK;Jansen MA;Japp AG;Newby DE;Dweck MR
• 通讯作者: Dweck MR

Comprehensive sequencing of dilated cardiomyopathy genes reveals additive effects of multiple genes on disease risk and severity

扩张型心肌病基因的综合测序揭示了多个基因对疾病风险和严重程度的叠加影响

• 作者: Mazzarotto F

CARDIOVASCULAR MAGNETIC RESONANCE IN SURVIVORS OF SUDDEN CARDIAC ARREST: 14 YEAR EXPERIENCE FROM A TERTIARY REFERRAL CENTRE IN THE UNITED KINGDOM

心脏骤停幸存者的心血管磁共振：英国三级转诊中心 14 年的经验

• DOI: 10.1016/s0735-1097(17)33880-9
• 发表时间: 2017
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Lota A

Response by Halliday et al to Letter Regarding Article, "Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients with Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction".

Halliday 等人对有关文章“扩张型心肌病和轻度和中度左心室收缩功能障碍患者中壁晚期钆增强与心脏猝死之间的关联”的信件的回应。

• DOI: 10.1161/circulationaha.117.032053
• 发表时间: 2018
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Halliday BP